Dendritic spines in excitatory synapses can undergo dynamic actin-based morphological changes associated with synaptic plasticity. Recent examination into the molecular basis of this plasticity uncovered a role for SPAR, a RapGAP that targets to the PSD of dendritic spines. In turn, SPAR stability is regulated by serine/threonine kinase SNK. SNK phosphorylates SPAR, which promotes SPAR degradation through a proteasomal pathway. Nevertheless, the identity of the E3 Ub-ligases that target SPAR and how they are regulated is still unknown. Our investigation into the E3 Ub-ligases that target SPAR to regulate synaptic plasticity includes the following three major efforts: Aim 1 investigates roles for SCF Ub-ligases in SPAR degradation and the activation signals they recognize in the substrate; Aim 2 details a comprehensive approach to identify all E3 Ub-ligases that target SPAR; and Aim 3 examines how depletion of identified candidate E3 Ub-ligases affects dendritic spine morphology in primary hippocampal neurons. In addition to providing concrete evidence for the involvement of the Ub-pathway in the regulation of dendritic spine morphology, identification of the E3 Ub-ligases that mediate SPAR degradation is intrinsic to understanding the mechanism that may underlie a number of disorders associated with abnormal spine morphology and density, including general mental retardation, fragile-X syndrome, Down's syndrome, and epilepsy.